Drug-loaded emulsion

ABSTRACT

The present invention relates to a drug-loaded emulsion, comprising a modified hydrophobic excipient having the following formula, a hydrophobic drug and a surfactant:where R is a hydrophobic natural compound or a hydrophobic synthetic compound with one to three hydroxyl groups (n=1-3); and R1 is an α-amino protecting group, and R2 is an amino acid side chain, wherein, when m=0, R is reacted with an amino acid derivative with a protecting group by esterification to form a hydrophobic excipient carrying the amino acid derivative with a protecting group; or when m=1, R is firstly introduced with an amino acid linking arm of different chain lengths (l=1, 2, 4, 6) via an ester group, and then introduced with an amino acid derivative with a protecting group.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of international PCT applicationserial no. PCT/CN2019/091964, filed on Jun. 19, 2019. The entirety ofthe above-mentioned patent application is hereby incorporated byreference herein and made a part of this specification.

TECHNICAL FIELD

The present application relates to the application field of preparationof pharmaceutical excipient and drug-loaded fat emulsion, in particularto a drug-loaded emulsion.

BACKGROUND ART

Many poorly water-soluble drugs require chemical or physical methods toincrease water solubility and have to be prepared as injections beforeuse. Drugs can be solubilized by chemical coupling with hydrophilic oramphiphilic excipients, or by preparation processes such as forming amolecular inclusion with cyclodextrin, forming a micelle,nano-dispersion and liposome with a surfactant, forming emulsion with asurfactant and an oil phase, and albumin wraping.

Emulsion is a commonly used drug carrier to increase the solubility ofpoorly water-soluble drugs, while protecting the drugs from rapiddegradation and altering the residence time of drugs in the blood andtissue distribution of drugs in the body. An emulsion is a dispersion ofa liquid oil phase stabilized by a layer of hydrophilic surfactant in anaqueous phase. Solid Lipid Nanoparticles particularly refer to adispersion of an oil phase stabilized by a layer of hydrophilicsurfactant and assuming a solid state at normal temperature in anaqueous phase. A drug-loaded emulsion usually uses natural or synthetictriglyceride, fatty acid ester, cholesterol oleate or medium- andlong-chain hydrocarbon as an oil phase, which have stronghydrophobicity. A drug has to be firstly well dissolved in a liquid oilphase before it can be prepared into a drug loaded emulsion is prepared.Therefore, the solubility of the drug in the oil phase is a keyparameter for determining the drug loading capacity of the emulsion andthe stability of the emulsion. However, many drugs have limitedsolubility in an oil phase having a strong hydrophobicity. Therefore,there will be very important practical significance to improve thesolubility of hydrophobic drugs in an oil phase.

SUMMARY

In view of the defects present in existing technologies, a first purposeof the present application is to provide a modified hydrophobicexcipient which has advantages of improving solubility of a drug in thehydrophobic excipient and increasing the drug loading capacity of thehydrophobic excipient.

In order to achieve the above purpose, the present application providesthe following technical solutions:

-   In a first aspect, a modified hydrophobic excipient is provided,    having the following molecular formula:

where R is a hydrophobic natural compound or hydrophobic syntheticcompound with one to three hydroxyl groups (n=1-3); R1 is an α-aminoprotecting group, and R2 is an amino acid side chain, wherein,

-   when m=0, R reacts with an amino acid derivative with a protecting    group by esterification to form a hydrophobic excipient carrying the    amino acid derivative with a protecting group; or-   when m=1, R is first introduced with an amino acid linking arm of    different chain lengths (l=1, 2, 4, 6) via an ester group, and then    introduced with an amino acid derivative with a protecting group.

In a further development of the first aspect of the present application,the hydrophobic natural compound or hydrophobic synthetic compound withone to three hydroxyl groups (n=1-3) includes a triglyceride with one tothree hydroxyl groups or a derivative thereof or a hydrophobicderivative of a steroid, or is obtained by introducing a hydroxyl groupinto an unsaturated triglyceride through an epoxy reaction and anelectrophilic reaction or by introducing a hydroxyl group into anunsaturated triglyceride through a Michael reaction under aphotocatalytic condition.

In a further development of the first aspect of the present application,the natural triglyceride with one to three hydroxyl groups is castoroil, and the derivative of the natural triglyceride with one to threehydroxyl groups is a hydrogenated derivative of castor oil.

In a further development of the first aspect of the present application,the hydrophobic derivative of the steroid is any one selected from agroup consisting of an ester derivative or an amide derivative of cholicacid, an ester derivative or an amide derivative of deoxycholic acid, anester derivative or an amide derivative of lithocholic acid, and anester derivative or an amide derivative of glycocholic acid.

In a further development of the first aspect of the present application,the derivatives of the amino acids are any one selected from a groupconsisting ofN-fluorenylmethoxy-carbonyl-N′-tert-butoxycarbonyl-L-lysine,N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-D-lysine,N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-L-lysine,N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-D-lysine,N-fluorenylmethoxycarbonyl-N′-benzyloxycarbonyl-L-lysine,N-fluorenylmethoxycarbonyl-N′-benzyloxycarbonyl-D-lysine,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-L-lysine,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-D-lysine,N-benzyloxycarbonyl-N′-benzyloxycarbonyl-L-lysine,N-benzyloxycarbonyl-N′-benzyloxycarbonyl-D-lysine,N-benzyloxycarbonyl-N′-fluorenylmethoxycarbonyl-L-lysine,N-benzyloxycarbonyl-N′-fluorenylmethoxycarbonyl-D-lysine,N-tert-butoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine,N-tert-butoxycarbonyl-N′-tert-butoxycarbonyl-D-lysine,N-tert-butoxycarbonyl-N′-fluorenylmethoxycarbonyl-L-lysine,N-tert-butoxycarbonyl-N′-fluorenylmethoxycarbonyl-D-lysine,N-tert-butoxycarbonyl-N′-benzyloxycarbonyl-L-lysine,N-tert-butoxycarbonyl-N′-benzyloxycarbonyl-D-lysine,N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-ornithine,N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-D-ornithine,N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-L-ornithine,N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-D-ornithine,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-L-ornithine,N-fluorenylmethoxycarbonyl-N′-benzyloxycarbonyl-L-ornithine,N-fluorenylmethoxycarbonyl-N′-benzyloxycarbonyl-D-ornithine,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-L-ornithine,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-D-ornithine,N-benzyloxycarbonyl-N′-benzyloxycarbonyl-L-ornithine,N-benzyloxycarbonyl-N′-benzyloxycarbonyl-D-ornithine,N-benzyloxycarbonyl-N′-fluorenylmethoxycarbonyl-L-ornithine,N-benzyloxycarbonyl-N′-fluorenylmethoxycarbonyl-D-ornithine,N-tert-butoxycarbonyl-N′-tert-butoxycarbonyl-L-ornithine,N-tert-butoxycarbonyl-N′-tert-butoxycarbonyl-D-ornithine,N-tert-butoxycarbonyl-N′-fluorenylmethoxycarbonyl-L-ornithine,N-tert-butoxycarbonyl-N′-fluorenylmethoxycarbonyl-D-ornithine,N-tert-butoxycarbonyl-N′-benzyloxycarbonyl-L-ornithine,N-tert-butoxycarbonyl-N′-benzyloxycarbonyl-D-ornithine,N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-tryptophan,N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-D-tryptophan,N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-L-tryptophan,N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-D-tryptophan,N-fluorenylmethoxycarbonyl-N′-benzyloxycarbonyl-L-tryptophan,N-fluorenylmethoxycarbonyl-N′-benzyloxycarbonyl-D-tryptophan,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-L-tryptophan,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-D-tryptophan,N-benzyloxycarbonyl-N′-benzyloxycarbonyl-L-tryptophan,N-benzyloxycarbonyl-N′-benzyloxycarbonyl-D-tryptophan,N-tert-butoxycarbonyl-N′-tert-butoxycarbonyl-L-tryptophan,N-tert-butoxycarbonyl-N′-tert-butoxycarbonyl-D-tryptophan,N-fluorenylmethoxycarbonyl-O′-benzyl ester-L-aspartic acid,N-fluorenylmethoxycarbonyl-O′-benzyl ester-D-aspartic acid,N-benzyloxycarbonyl-O′-benzyl ester-L-aspartic acid,N-benzyloxycarbonyl-O′-benzyl ester-D-aspartic acid,N-tert-butoxycarbonyl-O′-benzyl ester-L-aspartic acid,N-tert-butoxycarbonyl-O′-benzyl ester-D-aspartic acid,N-tert-butoxycarbonyl-O-benzyl ester-L-aspartic acid,N-tert-butoxycarbonyl-O-benzyl ester-D-aspartic acid,N-fluorenylmethoxycarbonyl-O′-methyl ester-L-aspartic acid,N-fluorenylmethoxycarbonyl-O′-methyl ester-D-aspartic acid,N-benzyloxycarbonyl-O′-methyl ester-L-aspartic acid,N-benzyloxycarbonyl-O′-methyl ester-D-aspartic acid,N-tert-butoxycarbonyl-O′-methyl ester-L-aspartic acid,N-tert-butoxycarbonyl-O′-methyl ester-D-aspartic acid,N-tert-butoxycarbonyl-O-methyl ester-L-aspartic acid,N-tert-butoxycarbonyl-O-methyl ester-D-aspartic acid,N-fluorenylmethoxycarbonyl-O′-ethyl ester-L-aspartic acid,N-fluorenylmethoxycarbonyl-O′-ethyl ester-D-aspartic acid,N-benzyloxycarbonyl-O′-ethyl ester-L-aspartic acid,N-benzyloxycarbonyl-O′-ethyl ester-D-aspartic acid,N-tert-butoxycarbonyl-O′-ethyl ester-L-aspartic acid,N-tert-butoxycarbonyl-O′-ethyl ester-D-aspartic acid,N-tert-butoxycarbonyl-O-ethyl ester-L-aspartic acid,N-tert-butoxycarbonyl-O-ethyl ester-D-aspartic acid,N-fluorenylmethoxycarbonyl-O′-tert-butyl ester-L-aspartic acid,N-fluorenylmethoxycarbonyl-O′-tert-butyl ester-D-aspartic acid,N-benzyloxycarbonyl-O′-tert-butyl ester-L-aspartic acid,N-benzyloxycarbonyl-O′-tert-butyl ester-D-aspartic acid,N-tert-butoxycarbonyl-O′-tert-butyl ester-L-aspartic acid,N-tert-butoxycarbonyl-O′-tert-butyl ester-D-aspartic acid,N-tert-butoxycarbonyl-O-tert-butyl ester-L-aspartic acid,N-tert-butoxycarbonyl-O -tert-butyl ester-D-aspartic acid,N-fluorenylmethoxycarbonyl-O′-allyl ester-L-aspartic acid,N-fluorenylmethoxycarbonyl-O′-allyl ester-D-aspartic acid,N-benzyloxycarbonyl-O′-allyl ester-L-aspartic acid,N-benzyloxycarbonyl-O′-allyl ester-D-aspartic acid,N-tert-butoxycarbonyl-O′-allyl ester-L-aspartic acid,N-tert-butoxycarbonyl-O′-allyl ester-D-aspartic acid,N-tert-butoxycarbonyl-O-allyl ester-L-aspartic acid,N-tert-butoxycarbonyl-O -allyl ester-D-aspartic acid,N-fluorenylmethoxycarbonyl-O′-benzyl ester-L-glutamic acid,N-fluorenylmethoxycarbonyl-O′-benzyl ester-D-glutamic acid,N-benzyloxycarbonyl-O′-benzyl ester-L-glutamic acid,N-benzyloxycarbonyl-O′-benzyl ester-D-glutamic acid,N-tert-butoxycarbonyl-O′-benzyl ester-L-glutamic acid,N-tert-butoxycarbonyl-O′-benzyl ester-D-glutamic acid,N-tert-butoxycarbonyl-O-benzyl ester-L-glutamic acid,N-tert-butoxycarbonyl-O-benzyl ester-D-glutamic acid,N-fluorenylmethoxycarbonyl-O′-methyl ester-L-glutamic acid,N-fluorenylmethoxycarbonyl-O′-methyl ester-D-glutamic acid,N-benzyloxycarbonyl-O′-methyl ester-L-glutamic acid,N-benzyloxycarbonyl-O′-methyl ester-D-glutamic acid,N-tert-butoxycarbonyl-O′-methyl ester-L-glutamic acid,N-tert-butoxycarbonyl-O′-methyl ester-D-glutamic acid,N-tert-butoxycarbonyl-O-methyl ester-L-glutamic acid,N-tert-butoxycarbonyl-O-methyl ester-D-glutamic acid,N-fluorenylmethoxycarbonyl-O′-ethyl ester-L-glutamic acid,N-fluorenylmethoxycarbonyl-O′-ethyl ester-D-glutamic acid,N-benzyloxycarbonyl-O′-ethyl ester-L-glutamic acid,N-benzyloxycarbonyl-O′-ethyl ester-D-glutamic acid,N-tert-butoxycarbonyl-O′-ethyl ester-L-glutamic acid,N-tert-butoxycarbonyl-O′-ethyl ester-D-glutamic acid,N-tert-butoxycarbonyl-O-ethyl ester-L-glutamic acid,N-tert-butoxycarbonyl-O-ethyl ester-D-glutamic acid,N-fluorenylmethoxycarbonyl-O′-tert-butyl ester-L-glutamic acid,N-fluorenylmethoxycarbonyl-O′-tert-butyl ester-D-glutamic acid,N-benzyloxycarbonyl-O′-tert-butyl ester-L-glutamic acid,N-benzyloxycarbonyl-O′-tert-butyl ester-D-glutamic acid,N-tert-butoxycarbonyl-O′-tert-butyl ester-L-glutamic acid,N-tert-butoxycarbonyl-O′-tert-butyl ester-D-glutamic acid,N-tert-butoxycarbonyl-O-tert-butyl ester-L-glutamic acid,N-tert-butoxycarbonyl-O-tert-butyl ester-D-glutamic acid,N-fluorenylmethoxycarbonyl-O′-allyl ester-L-glutamic acid,N-fluorenylmethoxycarbonyl-O′-allyl ester-D-glutamic acid,N-benzyloxycarbonyl-O′-allyl ester-L-glutamic acid,N-benzyloxycarbonyl-O′-allyl ester-D-glutamic acid,N-tert-butoxycarbonyl-O′-allyl ester-L-glutamic acid,N-tert-butoxycarbonyl-O′-allyl ester-D-glutamic acid,N-tert-butoxycarbonyl-O-allyl ester-L-glutamic acid,N-tert-butoxycarbonyl-O-allyl ester-D-glutamic acid,N-fluorenylmethoxycarbonyl-L-asparagine,N-fluorenylmethoxycarbonyl-D-asparagine,N-benzyloxycarbonyl-L-asparagine, N-benzyloxycarbonyl-D-asparagine,N-tert-butoxycarbonyl-L-asparagine, N-tert-butoxycarbonyl-D-asparagine,N-fluorenylmethoxycarbonyl-L-glutamine,N-fluorenylmethoxycarbonyl-D-glutamine, N-benzyloxycarbonyl-L-glutamine,N-benzyloxycarbonyl-D-glutamine, N-tert-butoxycarbonyl-L-glutamine,N-tert-butoxycarbonyl-D-glutamine,N-fluorenylmethoxycarbonyl-O-acetyl-L-serine,N-fluorenylmethoxycarbonyl-O-acetyl-D-serine,N-benzyloxycarbonyl-O-acetyl-L-serine,N-benzyloxycarbonyl-O-acetyl-D-serine,N-tert-butoxycarbonyl-O-acetyl-L-serine,N-tert-butoxycarbonyl-O-acetyl-D-serine,N-fluorenylmethoxycarbonyl-O-benzyl-L-serine,N-fluorenylmethoxycarbonyl-O-benzyl-D-serine,N-benzyloxycarbonyl-O-benzyl-L-serine,N-benzyloxycarbonyl-O-benzyl-D-serine,N-tert-butoxycarbonyl-O-benzyl-L-serine,N-tert-butoxycarbonyl-O-benzyl-D-serine,N-fluorenylmethoxycarbonyl-O-tert-butyl-L-serine,N-fluorenylmethoxycarbonyl-O-tert-butyl-D-serine,N-benzyloxycarbonyl-O-tert-butyl-L-serine,N-benzyloxycarbonyl-O-tert-butyl-D-serine,N-tert-butoxycarbonyl-O-tert-butyl-L-serine,N-tert-butoxycarbonyl-O-tert-butyl-D-serine,N-fluorenylmethoxycarbonyl-O-allyl-L-serine,N-fluorenylmethoxycarbonyl-O-allyl-D-serine,N-benzyloxycarbonyl-O-allyl-L-serine,N-benzyloxycarbonyl-O-allyl-D-serine,N-tert-butoxycarbonyl-O-allyl-L-serine;N-tert-butoxycarbonyl-O-allyl-D-serine;N-fluorenylmethoxycarbonyl-O-acetyl-L-threonine,N-fluorenylmethoxycarbonyl-O-acetyl-D-threonine,N-benzyloxycarbonyl-O-acetyl-L-threonine,N-benzyloxycarbonyl-O-acetyl-D-threonine,N-tert-butoxycarbonyl-O-acetyl-L-threonine,N-tert-butoxycarbonyl-O-acetyl-D-threonine,N-fluorenylmethoxycarbonyl-O-benzyl-L-threonine,N-fluorenylmethoxycarbonyl-O-benzyl-D-threonine,N-benzyloxycarbonyl-O-benzyl-L-threonine,N-benzyloxycarbonyl-O-benzyl-D-threonine,N-tert-butoxycarbonyl-O-benzyl-L-threonine,N-tert-butoxycarbonyl-O-benzyl-D-threonine,N-fluorenylmethoxycarbonyl-O-tert-butyl-L-threonine,N-fluorenylmethoxycarbonyl-O-tert-butyl-D-threonine,N-benzyloxycarbonyl-O-tert-butyl-L-threonine,N-benzyloxycarbonyl-O-tert-butyl-D-threonine,N-tert-butoxycarbonyl-O-tert-butyl-L-threonine,N-tert-butoxycarbonyl-O-tert-butyl-D-threonine,N-fluorenylmethoxycarbonyl-O-allyl-L-threonine,N-fluorenylmethoxycarbonyl-O-allyl-D-threonine,N-benzyloxycarbonyl-O-allyl-L-threonine,N-benzyloxycarbonyl-O-allyl-D-threonine,N-tert-butoxycarbonyl-O-allyl-L-threonine,N-tert-butoxycarbonyl-O-allyl-D-threonine,N-fluorenylmethoxycarbonyl-NG-2,2,4,6,7-pentamethylbenzofuran-5-sulfonyl-L-arginine,N-fluorenylmethoxycarbonyl-NG-2,2,4,6,7-pentamethylbenzofuran-5-sulfonyl-D-arginine,N-benzyloxycarbonyl-NG-2,2,4,6,7-pentamethylbenzofuran-5-sulfonyl-L-arginine,N-benzyloxycarbonyl-NG-2,2,4,6,7-pentamethylbenzofuran-5-sulfonyl-D-arginine,N-tert-butoxycarbonyl-NG-2,2,4,6,7-pentamethylbenzofuran-5-sulfonyl-L-arginine,N-tert-butoxycarbonyl-NG-2,2,4,6,7-pentamethylbenzofuran-5-sulfonyl-D-arginine,N-fluorenylmethoxycarbonyl-N′-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine,N-fluorenylmethoxycarbonyl-N′-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-D-arginine,N-benzyloxycarbonyl-N′-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine,N-benzyloxycarbonyl-N′-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-D-arginine,N-tert-butoxycarbonyl-N′-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-L-arginine,N-tert-butoxycarbonyl-N′-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-D-arginine,N-fluorenylmethoxycarbonyl-glycine, N-benzyloxycarbonyl-glycine,N-tert-butoxycarbonyl-glycine, N-fluorenylmethoxycarbonyl-β-alanine,N-benzyloxycarbonyl-β-alanine, N-tert-butoxycarbonyl-β-alanine,N-fluorenylmethoxycarbonyl-L-valine,N-fluorenylmethoxycarbonyl-D-valine, N-benzyloxycarbonyl-L-valine,N-benzyloxycarbonyl-D-valine, N-tert-butoxycarbonyl-L-valine,N-tert-butoxycarbonyl-D-valine, N-tert-butyloxycarbonyl-L-alanine,N-fluoromethoxycarbonyl-D-alanine, N-benzyloxycarbonyl-L-alanine,N-benzyloxycarbonyl-D-alanine, N-tert-butoxycarbonyl-L-alanine,N-tert-butoxycarbonyl-D-alanine, N-fluorenylmethoxycarbonyl-L-leucine,N-fluorenylmethoxycarbonyl-D-leucine, N-benzyloxycarbonyl-L-leucine,N-benzyloxycarbonyl-D-leucine, N-tert-butoxycarbonyl-L-leucine,N-tert-butoxycarbonyl-D-leucine,N-fluorenylmethoxycarbonyl-L-isoleucine,N-fluorenylmethoxycarbonyl-D-isoleucine,N-benzyloxycarbonyl-L-isoleucine, N-benzyloxycarbonyl-D-isoleucine,N-tert-butoxycarbonyl-L-isoleucine, N-tert-butoxycarbonyl-D-isoleucine,N-fluorenylmethoxycarbonyl-L-methionine,N-fluorenylmethoxycarbonyl-D-methionine,N-benzyloxycarbonyl-L-methionine, N-benzyloxycarbonyl-D-methionine,N-tert-butoxycarbonyl-L-methionine, N-tert-butoxycarbonyl-D-methionine,N-fluorenylmethoxycarbonyl-L-tyrosine,N-fluorenylmethoxycarbonyl-D-tyrosine, N-benzyloxycarbonyl-L-tyrosine,N-benzyloxycarbonyl-D-tyrosine, N-tert-butoxycarbonyl-L-tyrosine,N-tert-butoxycarbonyl-D-tyrosine,N-fluorenylmethoxycarbonyl-L-acetyltyrosine,N-fluorenylmethoxycarbonyl-D-acetyltyrosine,N-benzyloxycarbonyl-L-acetyltyrosine,N-benzyloxycarbonyl-D-acetyltyrosine,N-tert-butoxycarbonyl-L-acetyltyrosine,N-tert-butoxycarbonyl-D-acetyltyrosine,N-fluorenylmethoxycarbonyl-L-phenylalanine,N-fluorenylmethoxycarbonyl-D-phenylalanine,N-benzyloxycarbonyl-L-phenylalanine,N-benzyloxycarbonyl-D-phenylalanine,N-tert-butoxycarbonyl-L-phenylalanine, andN-tert-butoxycarbonyl-D-phenylalanine.

In a further development of the first aspect of the present application,the amino protecting group is any one selected from a group consistingof fluorenylmethoxycarbonyl (Fmoc group), benzyloxycarbonyl (Cbz group),tert-butyloxycarbonyl (Boc group), benzoyl, formyl, acetyl ortrifluoroacetyl group.

In a further development of the first aspect of the present application,the amino acid derivative is a glycine derivative or a lysinederivative.

In a further development of the first aspect of the present application,the glycine derivative is selected from a group consisting ofN-fluorenylmethoxycarbonyl-glycine, N-benzyloxycarbonyl-glycine andN-tert-butoxycarbonyl-glycine, and the lysine derivative is selectedfrom a group consisting of

N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine,N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-D-lysine,N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-L-lysine,N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-D-lysine,N-fluorenylmethoxycarbonyl-N′-benzyloxycarbonyl-L-lysine,N-fluorenylmethoxycarbonyl-N′-benzyloxycarbonyl-D-lysine,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-L-lysine,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-D-lysine,N-benzyloxycarbonyl-N′-benzyloxycarbonyl-L-lysine,N-benzyloxycarbonyl-N′-benzyloxycarbonyl-D-lysine,N-benzyloxycarbonyl-N′-fluorenylmethoxycarbonyl-L-lysine,N-benzyloxycarbonyl-N′-fluorenylmethoxycarbonyl-D-lysine,N-tert-butoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine,N-tert-butoxycarbonyl-N′-tert-butoxycarbonyl-D-lysine,N-tert-butoxycarbonyl-N′-fluorenylmethoxycarbonyl-L-lysine,N-tert-butoxycarbonyl-N′-fluorenylmethoxycarbonyl-D-lysine,N-tert-butoxycarbonyl-N′-benzyloxycarbonyl-L-lysine, andN-tert-butoxycarbonyl-N′-benzyloxycarbonyl-D-lysine.

In a second aspect, the present application provides a hydrophobicexcipient having the following formula:

where R is a triglyceride with one to three hydroxyl groups (n=1-3) or aderivative of the triglyceride with one to three hydroxyl groups or ahydrophobic derivative of a steroid, R1 is any one selected from a groupconsisting of fluorenylmethoxycarbonyl (Fmoc group) or benzyloxycarbonyl(Cbz group) or tert-butoxycarbonyl (Boc group) or benzoyl or formyl oracetyl or trifluoroacetyl group, and R2 is an amino acid side chain;wherein, when m=0, R is reacted with an amino acid derivative withfluorenylmethoxycarbonyl (Fmoc group) or benzyloxycarbonyl (Cbz group)or tert-butyloxycarbonyl (Boc group) or benzoyl or formyl or acetyl ortrifluoroacetyl protecting group through esterification to form thehydrophobic excipient; or when m=1, R is firstly introduced with anamino acid linking arm of different chain lengths (l=1, 2, 4, 6) via anester group, and then introduced with a glycine derivative or a lysinederivative with a protecting group such as fluorenylmethoxycarbonyl(Fmoc group), benzyloxycarbonyl (Cbz group), tert-butyloxycarbonyl (Bocgroup), benzoyl, formyl, acetyl or trifluoroacetyl group to form thehydrophobic excipient.

In a further development of the second aspect of the presentapplication, the natural triglyceride with one to three hydroxyl groupsinclude castor oil; and the derivatives of natural triglycerides withone to three hydroxyl group includes hydrogenated derivatives of castoroil.

In a further development of the second aspect of the presentapplication, the hydrophobic derivative of the steroid is selected froma group consisting of ester derivatives or amide derivatives of cholicacid, ester derivatives or amide derivatives of deoxycholic acid, esterderivatives or amide derivatives of lithocholic acid, and esterderivatives or amide derivatives of glycocholic acid.

In a further development of the second aspect of the presentapplication, the amide derivative of cholic acid is cholicacid-N-oleylamine.

In a further development of the second aspect of the presentapplication, the glycine derivative is selected from a group consistingof N-fluorenylmethoxycarbonyl-glycine, N-benzyloxycarbonyl-glycine andN-tert-butoxycarbonyl-glycine; and the lysine derivative is selectedfrom a group consisting of

N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine,N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-D-lysine,N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-L-lysine,N-benzyloxycarbonyl-N′-tert-butoxycarbonyl-D-lysine,N-fluorenylmethoxycarbonyl-N′-benzyloxycarbonyl-L-lysine,N-fluorenylmethoxycarbonyl-N′-benzyloxycarbonyl-D-lysine,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-L-lysine,N-fluorenylmethoxycarbonyl-N′-fluorenylmethoxycarbonyl-D-lysine,N-benzyloxycarbonyl-N′-benzyloxycarbonyl-L-lysine,N-benzyloxycarbonyl-N′-benzyloxycarbonyl-D-lysine,N-benzyloxycarbonyl-N′-fluorenylmethoxycarbonyl-L-lysine,N-benzyloxycarbonyl-N′-fluorenylmethoxycarbonyl-D-lysine,N-tert-butoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine,N-tert-butoxycarbonyl-N′-tert-butoxycarbonyl-D-lysine,N-tert-butoxycarbonyl-N′-fluorenylmethoxycarbonyl-L-lysine,N-tert-butoxycarbonyl-N′-fluorenylmethoxycarbonyl-D-lysine,N-tert-butoxycarbonyl-N′-benzyloxycarbonyl-L-lysine, andN-tert-butoxycarbonyl-N′-benzyloxycarbonyl-D-lysine.

In a further development of the second aspect of the presentapplication, the glycine derivative is selected from a group consistingof N-fluorenylmethoxycarbonyl-glycine, N-benzyloxycarbonyl-glycine andN-tert-butoxycarbonyl-glycine, and the lysine derivative isN-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine.

The technical solution is designed based on the principle as follows.The conventional hydrophobic excipients mainly dissolve and load ahydrophobic drug in a hydrophobic excipient through hydrophobic effect.However, since the solubility of the hydrophobic drug in the hydrophobicexcipient with extremely strong hydrophobicity is limited, thehydrophobic drug tends to be crystallized and separated out whenexceeding the solubility of the hydrophobic drug. In view of the factthat a plurality of hydrophobic drugs have aromatic benzene rings orderivatives thereof or heterocycles in the structure, introducing anamino acid with aromatic rings into hydrophobic excipients with one ormore hydroxyl groups will provide the modified hydrophobic excipientswith a function, which is beneficial for the stacking of aromatic groupsbetween the modified hydrophobic excipients and drugs containingaromatic groups. Further, most of the hydrophobic drugs generallycontain chemical bonds capable of forming hydrogen bonds, therefore,noncovalent physical interactions can occur between the carbamoyl groupsand amide groups on the amino acid derivatives and the drugs viahydrogen bonds. Due to the two kinds of extra molecular reactions, themodified hydrophobic excipient is favorable for improving thecompatibility with the hydrophobic drug, so that the solubility of thedrug is favorably increased, the stability of the drug-loaded fatemulsion is favorably improved, and meanwhile, the application range ofthe drug loading of the modified hydrophobic excipient is wider. Inorder to overcome possible steric hindrance, an amino acid linking armwith different chain lengths can be introduced into the hydrophobicexcipients with one or more hydroxyl groups through an ester group, andthen the amino acid with aromatic rings is introduced into the aminoacid linking arm.

In view of the defects present in existing technologies, a secondpurpose of the present application is to provide a preparation method ofa modified hydrophobic excipient, and the prepared modified hydrophobicexcipient has advantages of being beneficial to improve the solubilityof the hydrophobic drug in the modified hydrophobic excipient.

In order to achieve the above purpose, the present application providesthe following technical solutions.

-   In a third aspect, the present application provides a method for    preparing the modified hydrophobic excipient according to the first    aspect, wherein a hydrophobic natural compound with one to three    hydroxyl groups or a hydrophobic synthetic compound with one to    three hydroxyl groups and an amino acid derivative acting as raw    material, a dehydrating agent and a catalyst are subjected to an    esterification reaction according to the following reaction formula    to obtain the modified hydrophobic excipient, where n is 1-3,

In the above technical solution, since the hydroxyl is a hydrophilicgroup, the carboxyl on the amino acid derivative is reacted with thehydroxyl on the hydrophobic natural compound with one to three hydroxylgroups or the hydrophobic synthetic compound with one to three hydroxylgroups to form an ester bond, which is beneficial to improve thehydrophobicity of the excipient. Further, the group containing anaromatic ring and the group containing carbamoyl or amide are introducedinto the hydrophobic excipient, and are combined with the hydrophobiccompounds through physical actions such as aromatic ring stacking,hydrogen bond and the like. Therefore, the compatibility of thehydrophobic excipient and the hydrophobic drug is favorably improved,the solubility of the drug is increased, and the stability of thedrug-loaded fat emulsion is improved, so that the application range ofthe hydrophobic excipient is expanded.

In a further development of the third aspect of the present application,the dehydrating agent can be any one selected from a group consisting ofdicyclohexylcarbodiimide, N,N′-diisopropyl carbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,diphenyl-phosphoryl azide, p-toluenesulfonyl azide, and the like.

In a further development of the third aspect of the present application,the catalyst can be any one selected from a group consisting of4-dimethylpyridine, immobilized 4-dimethylpyridine and pyridine.

In a further development of the third aspect of the present application,the dehydrating agent is any one selected from a group consisting ofdicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and the catalyst isany one selected from a group consisting of 4-dimethylaminopyridine(DMAP) and immobilized DMAP.

In the above technical solution, the dicyclohexylcarbodiimide ordiisopropylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideas a dehydrating agent is cooperated with 4-dimethylaminopyridine orimmobilized DMAP as a catalyst, so that the activity of the reaction isimproved, and the reaction rate is accelerated.

In view of the defects present in existing technologies, the thirdpurpose of the present application is to provide a preparation method ofthe modified hydrophobic excipient, which has the advantage that theprepared modified hydrophobic excipient is beneficial to improving thesolubility of the hydrophobic drug in the hydrophobic excipient.

In order to achieve the above purpose, the present application providesthe following technical solutions:

-   In a fourth aspect, the present application provides a method for    preparing the modified hydrophobic excipient according to the second    aspect, including the following steps:-   Step A. subjecting a hydrophobic natural compound with one to three    hydroxyl groups or a hydrophobic synthetic compound with one to    three hydroxyl groups and amino acid derivatives with    N-tert-butyloxycarbonyl protecting group or N-benzyloxycarbonyl    protecting group acting as raw materials, a dehydrating agent and a    catalyst to an esterification reaction to generate intermediate I of    amino acid derivatives with N-tert-butyloxycarbonyl protecting group    or N-benzyloxycarbonyl protecting group, and adding an organic acid    or an inorganic acid to the amino acid derivatives with    N-tert-butyloxycarbonyl protecting group to remove the amino    protecting group or catalytically hydrogenating the amino acid    derivatives with N-benzyloxycarbonyl protecting group to remove the    amino protecting group, so as to obtain intermediate II with amino    groups, according to the following reaction formula, where R3 is an    α-amino protecting group, n is 1-3, and l=1, 2, 4, 6;

-   Step B. subjecting an amino acid derivative and N-hydroxysuccinimide    or 1-hydroxybenzotriazole acting as raw material and a dehydrating    agent to an esterification reaction to obtain intermediate III,    according to the following reaction formula, where R1 is an    alpha-amino protecting group, and R2 is an amino acid side chain;    and

-   Step C. reacting the intermediate II and the intermediate III as raw    materials with an acid-binding agent under a dark condition to    obtain a modified hydrophobic excipient, according to the following    reaction formula, where, n is 1-3, and l is 1, 2, 4 and 6.

In the above technical solution, the hydroxyl on the hydrophobicexcipient is modified by the protected amino acid, and then the aminoprotecting group is removed to form the intermediate II carrying anamino group. Thereby, a small intermolecular arm is introduced onto thehydrophobic excipient, which can the problem of incomplete couplingreaction due to steric hindrance. Carboxyl on the amino acid derivativeis activated firstly by N-hydroxysuccinimide or 1-hydroxybenzotriazoleto form N-hydroxysuccinimide or 1-hydroxybenzotriazole active ester(intermediate III) of the amino acid derivative, and thus can be easilybonded with amino on hydrophobic excipient amino acid ester. Thereaction of the intermediate II and the intermediate III provides thegenerated hydrophobic excipient with both an aromatic ring substituentgroup and a carbamoyl group or an amide group. Therefore, thehydrophobic excipient can be favorably combined with a hydrophobiccompound through the carried aromatic ring-containing group and thecarried carbamoyl group or amide group through non-covalent physicalactions such as aromatic ring stacking, hydrogen bond and the like. Inturn, the compatibility of the hydrophobic excipient and a hydrophobicdrug is favorably increased, the solubility of the drug is increased,and the stability of the drug-loaded fat emulsion is improved. Thus, thehydrophobic excipient can be combined with various hydrophobic drugs,and the application range of the hydrophobic excipient is favorablyexpanded.

In a further development of the fourth aspect of the presentapplication, the dehydrating agent can be any one selected from a groupconsisting of dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,diphenylphosphoryl azide, p-toluenesulfonyl azide, and the like.

In a further development of the fourth aspect of the presentapplication, the catalyst can be any one selected from a groupconsisting of 4-dimethyl pyridine, immobilized 4-dimethyl pyridine,pyridine, and the like.

In a further development of the fourth aspect of the presentapplication, the acid-binding agent can be any one selected from a groupconsisting of triethylamine, diisopropylamine, pyridine, and the like.

In a further development of the fourth aspect of the presentapplication, the dehydrating agent is dicyclohexylcarbodiimide, and thecatalyst is 4-dimethylaminopyridine.

In the above technical solution, dicyclohexylcarbodiimide as thedehydrating agent is cooperated with 4-dimethylaminopyridine as thecatalyst, so that the activity of the reaction is improved, the reactionrate is accelerated, and the post-treatment of the reaction isfacilitated.

In a further development of the fourth aspect of the presentapplication, in Step A, the catalytic hydrogenation reaction conditionis H₂(1-5 atm) and Pt/C as catalyst.

In the above technical solution, the catalyst used for removing theN-benzyloxycarbonyl by catalytic hydrogenation is 5% palladium carbon(Pt/C), and the dosage of the catalyst is 1-10%. The hydrogen pressureis 1-5 atm, and the reaction time is 1-12 hours at room temperature.When N-benzyloxycarbonyl is removed by catalytic hydrogenation, a properamount of acetic acid can be added for neutralizing newly generatedamino groups and preventing the amino groups from participating in aside reaction and inhibiting the activity of the catalyst.

In a further development of the fourth aspect of the presentapplication, in Step A, the amino protecting group isN-tert-butyloxycarbonyl or N-benzyloxycarbonyl, wherein theN-tert-butyloxycarbonyl and the N-benzyloxycarbonyl are removed by acidor catalytic hydrogenation respectively, and the intermediate I isdissolved in a solvent before adding the acid or performinghydrogenation.

In the above technical solution, dissolving the intermediate I in asolvent before adding the acid or performing hydrogen is beneficial tothe complete dissolution of the intermediate I, such that theintermediate I can better react with the organic acid or the inorganicacid, and the conversion efficiency can be improved.

In a further development of the fourth aspect of the presentapplication, the solvent can be any one selected from a group consistingof dichloromethane, ethyl acetate or tetrahydrofuran.

In a further development of the fourth aspect of the presentapplication, the acid-binding agent is triethylamine.

In the above technical solution, by using the triethylamine as theacid-binding agent, the reaction activity of the intermediate II and theintermediate III is favorably improved, and the modified hydrophobicexcipient is easier to generate.

In view of the defects present in existing technologies, a fourthpurpose of the present application is to provide a use of the modifiedhydrophobic excipient as an oil phase excipient, which can increase thesolubility of the hydrophobic drug in the modified hydrophobicexcipient, and can be combined with a proper surfactant to improve thedrug loading capacity and the stability of the drug-loaded fat emulsion.

In a fifth aspect, to achieve the above object, the present applicationprovides a technical solution of a drug-loaded emulsion composed of themodified hydrophobic excipient according to the first or second aspect,a hydrophobic drug and a surfactant. The modified hydrophobic excipient,the hydrophobic drug and the surfactant are dissolved in a propersolvent, the solvent is removed, a buffer solution is added forhydration, and the drug-loaded fat emulsion can be prepared by a properpreparation method.

In a further development of the fifth aspect of the present application,the modified hydrophobic excipient is protected amino acid ester of thehydrophobic excipient or protected amino acid amide of the hydrophobicexcipient amino acid ester.

In a further development of the fifth aspect of the present application,the hydrophobic drugs are paclitaxel, docetaxel and other hydrophobicdrugs which may have intermolecular interaction with the modifiedhydrophobic excipients such as aromatic ring stacking, hydrogen bond orhydrophobic interaction.

In a further development of the fifth aspect of the present application,the ratio between the hydrophobic drug and the modified hydrophobicexcipient may be any proper ratio, for example, 0.01% (w/w)-99.9% (w/w)to 99.9% (w/w)-0.01(w/w), a preferred ratio between the hydrophobic drugand the modified hydrophobic excipient is 1% (w/w)-50% (w/w) to 99%(w/w)-50(w/w), and a more preferred ratio between the hydrophobic drugand the modified hydrophobic excipient is 1:1 to 1:5.

In a further development of the fifth aspect of the present application,the surfactant may be any pharmaceutical excipient belonging to theclass of surfactants.

In a further development of the fifth aspect of the present application,the surfactant may be any pharmaceutical excipient of the class ofsurfactants having a hydrophilic-lipophilic balance (HLB) value in therange of 0 to 40.

In a further development of the fifth aspect of the present application,the surfactant can be any small molecule or large moleculepharmaceutical excipient with the functions of solubilizing oremulsifying or wetting or foaming agent or defoaming agent or detergent.

In a further development of the fifth aspect of the present application,the surfactant can be any small molecule or large moleculepharmaceutical excipient with the function of stabilizing the nanometerstructure.

In a further development of the fifth aspect of the present application,the surfactant may be a cationic or anionic or nonionic surfactant.

In a further development of the fifth aspect of the present application,the surfactant can be phospholipid or cholesterol, or fatty acid withthe chain length of C8-C22, or fatty acid salt with the chain length ofC8-C22, sucrose fatty acid ester, sorbitan fatty acid (spans),polysorbate (Tweens) polyoxyethylene fatty acid ester (Myrij),polyoxyethylene fatty alcohol ether, or PEG-cholesterol derivative withdifferent chain lengths, PEG-vitamin E succinate with different chainlengths, or PEG-phospholipid derivative with different chain lengths, orPEG-diglyceride derivative with different chain lengths, or any naturalpolymer pharmaceutical excipient or synthetic polymer pharmaceuticalexcipient with surface activity.

In a further development of the fifth aspect of the present application,the surfactant phospholipid can be any one selected from a groupconsisting of the following compounds, but not limited to,phosphatidylcholine (PC), Phosphatidylglycerol (PG),phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidicacid (PA), phosphatidylinositol (PI), eggphosphatidylcholine (EPC), eggphosphatidylglycerol (EPG), phosphatidylethanolamine (EPE),eggphosphatidylserine (EPS), egg phosphatidic acid (EPA), (eggphosphatidylinositol (EPI), soy phosphatidylcholine (SPC), soyphosphatidylglycerol (SPG), soyphosphatidylethanolamine (SPE), soyphosphatidylserine (SPS), (soy phosphatidic acid SPA), soyphosphatidylinositol (SPI), dipalmitoylphosphatidylcholine (DPPC),1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC),dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylglycerol(DPPG), dioleoylphosphatidylglycerol (DOPG),dimyristoylphosphatidylglycerol (DMPG), hexadecylphosphocholine (HEPC),hydrogenated soyphosphatidylcholine (HSPC),distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol(DSPG), dioleoylphosphatidylethanolamine (DSPE),palmitoylstearoylphosphatidylcholine (PSPC),palmitoylstearoylphosphatidylglycerol (PSPG),monooleoylphosphatidylethanolamine (MOPE),1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC),distearoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylserine(DPPS), 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS),dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine(DSPS), dipalmitoylphosphatidicacid (DPPA),1,2-dioleoyl-snglycero-3-phosphatidic acid (DOPA),dimyristoylphosphatidic acid (DMPA), distearoylphosphatidic acid (DSPA),dipalmitoylphosphatidylinositol (DPPI),1,2-dioleoylsn-glycero-3-phosphatidylinositol (DOPI),dimyristoylphosphatidylinositol (DMPI), distearoylphosphatidylinositol(DSPI), and mixtures of the foregoing phospholipids.

In a further development of the fifth aspect of the present application,the polyethylene glycol (PEG) with different chain lengths-the lipidderivative with the chain length of C8-C22, can be any surfactant formedby connecting PEG with the chain length of 1-1000 repeating units andlipid with the chain length of C8-C22 by ester bonds or ether bonds oramide bonds.

In a further development of the fifth aspect of the present application,the PEG-phospholipid derivatives with different chain lengths aresurfactants formed by connecting PEG with the chain length of 1-1000repeating units and natural or synthetic phospholipid by an ester bond,an amide bond or a carbamoyl bond.

In a further development of the fifth aspect of the present application,in the PEG-phospholipid derivatives with different chain lengths,prepared by connecting PEG with the chain length of 1-1000 repeatingunits with natural or synthetic phospholipids through ester bonds oramide bonds or carbamoyl bonds to obtain the surfactants, the natural orsynthetic phospholipids can be natural or synthetic phospholipids with acarbon chain length of 12-22.

In a further development of the fifth aspect of the present application,in the PEG-phospholipid derivatives with different chain lengths,prepared by connecting PEG with the chain length of 1-1000 repeatingunits with natural or synthetic phospholipids through ester bonds oramide bonds or carbamoyl bonds to obtain the surfactants, the natural orsynthetic phospholipids can be natural or synthetic phospholipid ofsaturated or unsaturated lipid chains with a carbon chain length of12-22.

In a further development of the fifth aspect of the present application,in the PEG-phospholipid derivatives with different chain lengths,prepared by connecting PEG with the chain length of 1-1000 repeatingunits with natural or synthetic phospholipids through ester bonds oramide bonds or carbamoyl bonds to obtain the surfactants, the natural orsynthetic phospholipids can be natural or synthetic cephalin.

In a further development of the fifth aspect of the present application,the natural polymer pharmaceutical excipient or synthetic polymerpharmaceutical excipient surfactant can be polysaccharide orpolysaccharide derivative or polyoxyethylene-polyoxypropylene(poloxamer) or protein with surface activity.

In a further development of the fifth aspect of the present application,the pharmaceutical excipient surfactant can be a single pharmaceuticalexcipient or a combination of multiple pharmaceutical excipientsurfactants by different proportions.

In a further development of the fifth aspect of the present application,the surfactant can be lecithin or cholesterol or PEG-phospholipidderivative single pharmaceutical excipient or a combination of multiplepharmaceutical excipient surfactants by different proportions.

In a further development of the fifth aspect of the present application,the surfactant can be combinations of lecithin and PEG-cephalinderivative by different proportions.

In the above technical solution, the blank fat emulsion can be preparedby adopting the modified hydrophobic excipient as the oil phase, incombintion with a combination of lecithin and PEG-cephalin derivativesby different proportions.

In addition, In the above technical solution, the drug-loaded fatemulsion can be prepared by adopting the modified hydrophobic excipientas the oil phase, in combination with a combination of the hydrophobicmedicament, lecithin and the PEG-cephalin derivative by differentproportions, so as to improve the drug-loaded amount and the stabilityof the drug-loaded fat emulsion.

In a further development of the fifth aspect of the present application,the proportion of the hydrophobic excipient-the hydrophobic drug to thesurface active excipient is (X+Y):Z, and Z %=100−(X+Y).

In a further development of the fifth aspect of the present application,the proportion of the hydrophobic excipient-the hydrophobic drug to thesurface active excipient is (X+Y):Z=(0-50%):(100-50%).

In the above technical solution, the drug-loaded fat emulsion can beprepared by different physical methods by adopting the modifiedhydrophobic excipient as the oil phase, in combination with acombination of hydrophobic medicament, the lecithin and PEG-cephalinderivatives by different proportions.

In a further development of the fifth aspect of the present application,the preparation method of the drug-loaded fat emulsion includes one or acombination of high-speed shearing, phase transition, high-pressurehomogenization, micro-jet and micro-fluidic methods.

In the above technical solution, the mixture of the hydrated hydrophobicexcipient, the hydrophobic drug and the surface active excipient aretreated by one or a combination of physical methods, so as to achievethe effect of effectively and controllably reducing the diameter of thefat emulsion.

In conclusion, the present application has the following beneficialeffects.

-   1. The modified hydrophobic excipient has a π-π function by    introducing an substituent group with an aromatic ring, so that the    modified hydrophobic excipient and the drug containing the aromatic    group can have aromatic ring stacking. Further, the carbamoyl group    and the amide group on the modified hydrophobic excipient can have a    non-covalent physical action with the drug through hydrogen bonds,    so that the solubility of the drug can be increased, and the    stability of the drug-loaded fat emulsion can be improved.-   2. The modified hydrophobic excipient can have a non-covalent    physical action with the drug through π-π and hydrogen bonds, so    that the modified hydrophobic excipient has a wider application    range of drug loading.-   3. The carboxyl on the amino acid derivative reacts with the    hydroxyl on the hydrophobic natural excipient with one to three    hydroxyl groups or the hydrophobic synthetic excipient with one to    three hydroxyl groups to form an ester bond. This is favorable for    increasing the hydrophobicity of the hydrophobic excipient, and, at    the same time, favorable for introducing an aromatic substituent    group and a carbamoyl group or an amide group onto the hydrophobic    excipient. This is also favorable for the hydrophobic excipient and    the drug containing the aromatic group to be combined with each    other through π-π aromatic ring stacking and non-covalent physical    action such as hydrogen bond, favorable for increasing the    solubility of the drug to improve the stability of the drug-loaded    fat emulsion, and is favorable for expanding the application range    of the hydrophobic excipient.-   4. Firstly preparing an amino acid ester of the hydrophobic    excipient and then introducing the protected amino acid by utilizing    the activated ester of the N-hydroxysuccinimide or the    1-hydroxybenzotriazole for protecting the amino acid is beneficial    for alleviating the problem of incomplete coupling reaction due to    steric hindrance, and at the same time, is favorable for forming the    hydrophobic excipient modified by the amino acid derivatives.-   5. Using the hydrophobic excipient as an oil phase excipient for    preparing the drug-loaded fat emulsion facilitates increasing the    solubility of a drug, and at the same time, increasing the    drug-loaded amount of the drug-loaded fat emulsion, and in turn the    stability of the drug-loaded fat emulsion.

DETAILED DESCRIPTION

The present application will be described in further detail withreference to examples.

EXAMPLE 1

A preparation method of a modified hydrophobic excipient was performedas follows:

9.34 g of castor oil (10 mmol), 29.5 g ofN-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine (60 mmol),366 mg of 4-dimethylaminopyridine (DMAP) (3 mmol) were added into a 250ml flask, then added with 12.4 g of dicyclohexylcarbodiimide (DCC)dissolved in 50 ml of anhydrous dichloromethane (60 mmol) and reacted atroom temperature under dark conditions for three days. After thereaction being completed, as indicated by TLC analysis, the reactionmixture was filtered to remove the precipitate, then spin-dried, andpurified by conventional purification to obtain a yellowish transparentviscous oily substance, which was cooled to obtain a glassy transparentsolid as a modified hydrophobic excipient. The reaction formula wasshown below. Castor oil is usually a mixture of triglycerides withdifferent ricinoleic acid content (n=0-3), and molecular formula thereofcannot be accurately illustrated. The following reaction formula, takingn=3 as an example, is used to illustrate the method principle of thepresent application without limiting the present application.

EXAMPLE 2

A preparation method of a hydrophobic excipient was performed asfollows:

A-1, castor oil-O-glycine triester was esterified byN-tert-butoxycarbonylglycine, and then was subjected to acidificationdeprotection by the following synthetic route:

9.34 g of castor oil (10 mmol), 7.2 g of N-t-butoxycarbonylglycine (45mmol), and 366 mg of 4-dimethylaminopyridine (DMAP) (3 mmol) were addedinto a 250 ml flask, then added with 12.4 g of N,N′-dicyclohexylcarbodiimide (DCC) (60 mmol) dissolved in 50 ml ofanhydrous dichloromethane, and reacted at room temperature under darkconditions for two days. After the reaction being completed, asindicated by TLC analysis, the reaction mixture was filtered to removethe precipitate, then spin-dried, and purified by conventionalpurification to obtain a colorless, transparent viscous oil, that is,the intermediate I, castor oil-O—(N-t-butoxycarbonylglycine) triester.

The intermediate I was dissolved in 40 ml of dichloromethane (DCM), thenadded with 40 ml of trifluoroacetic acid (TFA), and reacted at roomtemperature for 4 hours, to remove the protecting group. After removingexcessive trifluoroacetic acid by spinning, 60 ml of dichloromethane wasadded to dissolve the product, then added with 10 g anhydrous sodiumcarbonate powder, and stirred for three days to obtain intermediate II,which was castor oil-O-glycine triester. The reaction formula was shownbelow. Castor oil is usually a mixture of triglycerides with differentricinoleic acid content (n=0-3), and molecular formula thereof cannot beaccurately illustrated. The following reaction formula, taking n=3 as anexample, is used to illustrate the method principle of the presentapplication without limiting the present application.

Or A-2, the castor oil-O-glycine triester were esterified byN-benzyloxycarbonyl glycine and then synthesized by a catalytichydrogenation deprotection synthetic route, which included the followingsteps:

9.34 g of castor oil (10 mmol), 8.6 g N-benzyloxycarbonylglycine (45mmol), and 366 mg of 4-dimethylaminopyridine (DMAP) (3 mmol) were addedto a 250 ml flask, then added with 12.4 g (60 mmol) ofdicyclohexylcarbodiimide (DCC) dissolved in 50 ml of anhydrousdichloromethane, and reacted for two days at room temperature under darkconditions. After the reaction being completed, as indicated by TLCanalysis, the reaction mixture was filtered to remove the precipitate,then spin-dried, and purified by conventional purification to obtain acolorless, transparent viscous oil, that is, the intermediate I, whichwas castor oil-O—(N-benzyloxycarbonylglycine) triester.

In a catalytic hydrogenation pressure reactor, 15 g of castoroil-O—(N-benzyloxycarbonylglycine) triester was added, and then addedwith 40 ml of methanol and 1 ml of glacial acetic acid (HOAC). Themixture was sufficiently stirred and dissolved, added with about 600 mgof 5% palladium on carbon (Pt/C), the headspace air was replaced withhydrogen under stirring, the hydrogen pressure was increased to 5 atm,the reaction was carried out at room temperature for 4 hours, thebenzyloxycarbonyl protecting group was removed, and the excess aceticacid was removed by rotary drying to obtain intermediate II, which wascastor oil-O-glycine triester acetate. The reaction formula was shownbelow. Castor oil is usually a mixture of triglycerides with differentricinoleic acid content (n=0-3), and molecular formula thereof cannot beaccurately illustrated. The following reaction formula, taking n=3 as anexample, is used to illustrate the method principle of the presentapplication without limiting the present application.

B. The synthesis ofN-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine-N-hydroxysuccinimideester was performed as follows:

24 g of N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine (50mmol) and 5.6 g (50 mmol) of N-hydroxysuccinimidein were added to a 250ml flask, and the starting material was dissolved in 40 ml oftetrahydrofuran (THF), then added with 12.4 g (60 mmol) ofdicyclohexylcarbodiimide (DCC) dissolved in 50 ml of methylene chloride,and reacted at room temperature for 1 hour. The reaction was filtered toremove the precipitate and then dried by spin-drying to obtainintermediate III, which wasN-fluorenylmethoxycarbonyl-N′-tert-butylcarbonyl-L-lysine-N-hydroxysuccinimideester. The reaction formula was shown below.

C. The synthesis of the hydrophobic excipients was performed as follows:

10.5 g of the intermediate II was dissolved in 100 ml of anhydrousdichloromethane, added with 15 ml of triethylamine (TEA), then addedwith 30 g of the intermediate III dissolved in 50 ml of dichloromethane,and reacted for three days under a dark condition. After the reactionbeing completed, as indicated by TLC analysis, the reaction mixture wasfiltered to remove the precipitate, then spin-dried, and purified byconventional purification to obtain a yellowish transparent viscous oilysubstance, which was cooled to obtain a glassy transparent solid as amodified hydrophobic excipient. The reaction formula was shown below.

EXAMPLE 3

A preparation method of a hydrophobic excipient was performed asfollows:

A. the synthesis of hydrogenated castor oil-O-glycine triester wasperformed as follows:

9.36 g of hydrogenated castor oil (10 mmol), 7.2 g ofN-tert-butoxycarbonylglycine (45 mmol), 366 mg of4-dimethylaminopyridine (DMAP) (3 mmol) were dissolved in 100 ml ofanhydrous dichloromethane (DCM) in a 250 ml flask, then added with 10.3g (50 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 50 ml ofanhydrous dichloromethane, refluxed at 45° C. and reacted for two daysunder dark conditions. After the reaction being completed, as indicatedby TLC analysis, the reaction mixture was filtered to remove theprecipitate, and then spin-dried to provide a residue. The residue wasrecrystallized from ethyl acetate to obtain a slightly yellowishtransparent oily substance, which was cooled to obtain white crystals,that is, the intermediate I, which was hydrogenated castoroil-O—(N-tert-butoxycarbonylglycine) triester.

The intermediate I was dissolved in 40 ml of dichloromethane, added with40 ml of trifluoroacetic acid (TFA), and reacted at room temperature for4 hours, to remove the protecting group. After removing excessivetrifluoroacetic acid by spinning, 60 ml of dichloromethane was added todissolve the product, the added with 10 g of anhydrous sodiumbicarbonate powder, and stirred for three days to obtain theintermediate II, which was hydrogenated castor oil-O-glycine triester.The reaction formula was shown below. Castor oil is usually a mixture,and molecular formula thereof cannot be accurately illustrated. Thefollowing reaction formula, taking n=3 as an example, is used toillustrate the method principle of the present application withoutlimiting the present application.

B. The synthesis ofN-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine-N-hydroxysuccinimideester was performed as follows:

24 g of N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine (50mmol) and 5.6 g (50 mmol) of N-hydroxysuccinimidein were added to a 250ml flask, dissolved in 40 ml of anhydrous tetrahydrofuran (THF), thenadded with 12.4 g (60 mmol) of dicyclohexylcarbodiimide (DCC) dissolvedin 50 ml of methylene chloride, reacted at room temperature for 1 hour,filtered to remove the precipitate and then dried by spin-drying toobtain the intermediate III which wasN-fluorenylmethoxycarbonyl-N′-tert-butylcarbonyl-L-lysine-N-hydroxysuccinimideester. The reaction formula was shown below.

C. The synthesis of the modified hydrophobic excipient was performed asfollows:

the intermediate II was dissolved in 100 ml of anhydrousdichloromethane, added with 15 ml of triethylamine (TEA), then addedwith the intermediate III dissolved in 50 ml of dichloromethane (DCM),refluxed at 45° C., and reacted for three days under a dark condition.After the reaction being completed, as indicated by TLC analysis, thereaction mixture was filtered to remove the precipitate, then spin-driedto obtain a residue. The residue was recrystallized from ethyl acetate,to obtain a slightly yellowish transparent oily substance, which wascooled to obtain white crystals, as the hydrophobic excipient. Thereaction formula was shown below.

EXAMPLE 4

A preparation method of a hydrophobic excipient was performed asfollows:

A. the synthesis of the cholesterol oleamide-O-glycine triester wasperformed as follows:

3.82 g of cholic acid (10 mmol) and 1.2 g of N-hydroxysuccinimide(11mmol) were added to a 250 ml flask, dissolved in 40 ml of anhydroustetrahydrofuran (THF), then added with 2.3 g of dicyclohexylcarbodiimide(DCC) (11 mmol), and reacted at room temperature for 2 hours to formcholic acid-N-hydroxysuccinimide active ester. After the reaction beingcompleted, as indicated by TLC analysis, the reaction was added with 2.8g of oleylamine (10 mmol) and 1.5 ml of triethylamine (TEA) (10 mmol),and reacted overnight. After the reaction being completed, as indicatedby TLC analysis, the reaction mixture was filtered to remove theprecipitate, then spin-dried, and purified by conventional purificationto obtain a colorless, transparent viscous oil, as the cholesterololeamide. The reaction formula was shown below.

7.2 g N-tert-butoxycarbonylglycine (45 mmol) was added to a 100 mlflask, dissolved in 100 ml of anhydrous dichloromethane (DCM), and addedwith 5.4 g (25 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 50ml of anhydrous dichloromethane, and reacted at room temperature for 0.5h to form N-tert-butoxycarbonylglycine anhydride. The reaction formulawas shown below.

Cholesterol oleamide produced in the above reaction and 122 mg of4-dimethylaminopyridine (DMAP) (1 mmol) were dissolved in 40 ml ofanhydrous dichloromethane (DCM), then added withN-tert-butoxycarbonylglycine anhydride produced in the above reaction,and reacted for 48 hours. After the reaction being completed, asindicated by TLC analysis, the intermediate I was obtained, which wascholesterol oleamide-O—(N-tert-butoxycarbonylglycine) triester.

The intermediate I was dissolved in 40 ml of dichloromethane, then addedwith 40 ml of trifluoroacetic acid (TFA), and reacted at roomtemperature for 4 h, to remove protecting groups. After removingexcessive trifluoroacetic acid by spinning, the obtained product wasdissolved in 60 ml of dichloromethane, then added with 10 g of anhydroussodium bicarbonate powder, and stirred for three days to obtain theintermediate II, which was cholestyryl oleylamine-O-glycine triester.The reaction formula was shown below. The reaction formula was shownbelow.

B. The synthesis ofN-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine-N-hydroxysuccinimideester was performed as follows:

24 g of N-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine (50mmol) and 5.6 g of N-hydroxysuccinimide (50 mmol) were dissolved in 40ml of anhydrous tetrahydrofuran (THF) in a 250 ml flask, added with 12.4g (60 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 50 ml ofdichloromethane, reacted at room temperature for 1 hour, and the mixturewas filtered to remove precipitates and then dried by spin-drying toobtain the intermediate III, which wasN-fluorenylmethoxycarbonyl-N′-tert-butoxycarbonyl-L-lysine-N-hydroxysuccinimideester. The reaction formula was shown below.

C. The synthesis of the hydrophobic excipients was performed as follows:

the intermediate II was dissolved in 100 ml of anhydrousdichloromethane, added with 15 ml of triethylamine (TEA), then addedwith the intermediate III dissolved in 50 ml of dichloromethane (DCM),and reacted for three days at room temperature under dark conditions.After the reaction being completed, as indicated by TLC analysis, thereaction mixture was filtered to remove the precipitate, thenspin-dried, and purified by conventional purification to obtain ayellowish transparent viscous oily substance, which was cooled to obtaina glassy transparent solid as a modified hydrophobic excipient. Thereaction formula was shown below.

EXAMPLE 5

The solubility of paclitaxel in olive oil, castor oil and thehydrophobic excipients prepared in the above examples was measured.

The specific experimental method was as follows. 0.5 ml of chloroformsolution of olive oil, castor oil and the hydrophobic excipientsprepared in the above examples were added to a 12 ml penicillin bottle,in which the mass percentage concentration of the chloroform solution ofthe hydrophobic excipients was 50%. The chloroform solution was mixedwith 0.5 ml of chloroform, from which 0.5 ml of diluent was taken andtwo-fold serial dilution was performed by using chloroform. Then 0.5 mlof a chloroform solution of paclitaxel (10 mg/ml) was added to theabove-mentioned sample after the two-fold serial dilution, and then leftin a hood to be naturally volatilized overnight. Crystal formation inthe dried sample was observed and recorded.

Experimental data of the solubility of paclitaxel in olive oil, castoroil and the hydrophobic excipients prepared in the above examples wereshown in Table 1.

TABLE 1 solubility of paclitaxel in olive oil, castor oil andhydrophobic excipients Hydrophobic excipient (mg) Olive oil Castor oilExample 1 Example 2 Example 4 0.98 + + + + + 1.95 + + + + +3.90 + + + + + 7.81 + + +/− − +/− 15.65 + + − − − 31.30 + + − − −62.50 + + − − − 125.00 + + − − − 250.00 + + − − − In Table 1, “+”indicates that crystals were precipitated, “−” indicates that nocrystals was precipitated, and “+/−” indicates that the solution wasslightly turbid.

The modified hydrophobic excipient obtained in example 3 was notincluded in the experiment because the modified hydrophobic excipientcrystallized out at room temperature, and the experimental results couldnot be directly observed by naked eyes.

According to the data comparison in table 1, the solubility ofpaclitaxel in examples 1,2 and 4 is greater than that in olive oil andcastor oil, which indicates that the hydrophobic excipient has π-πfunction by introducing the substituent group with aromatic ringfluorene, which is beneficial to the aromatic ring accumulation betweenthe hydrophobic excipients and the drug containing aromatic group. Inaddition, the carbamoyl group and amide group on the hydrophobicexcipient can have non-covalent physical action with the drug throughhydrogen bond, and the compatibility of the hydrophobic excipient andthe hydrophobic drug can be improved through the above two additionalmolecular effects, thereby being beneficial to increasing the solubilityof the drug.

EXAMPLE 6

Blank, paclitaxel and docetaxel drug-loaded fat emulsions were prepared,and detected for the stability of the drug-loaded fat emulsion, whichcomprised the following steps:

Experiment 6.1

Blank fat emulsion: 1.5 mg of castor oil, 0.2 mg of egg yolk lecithin,0.4 mg of mPEG2000-DSPE were dissolved in chloroform, blown to dry innitrogen and dried under vacuum. Then 1 ml of phosphate buffer solutionwas added to adjust pH to 7.4, hydrated for 1 h, homogenized for 5 minat 20000 r/min with high speed shearing machine. The obtained blank fatemulsion was detected by Malvern ZS laser particle size analyzer, andthe average particle size thereof was 200 nm.

Experiment 6.2

Paclitaxel-castor oil drug-loaded fat emulsion: 100 mg of paclitaxel,300 mg of castor oil, 40 mg of egg yolk lecithin, and 80 mg ofmPEG2000-DSPE were dissolved in chloroform, blown to dry in nitrogen anddried under vacuum. Then 20 ml of phosphate buffer solution was added toadjust pH to 7.4, hydrated for 1 h, homogenized for 5 min at 20000 r/minwith high speed shearing machine. The obtained drug-loaded fat emulsionwas detected by Malvern ZS laser particle size analyzer, and the averageparticle size thereof was 280 nm. The drug-loaded fat emulsion can beonly stable for a short period of time after preparation, whiteprecipitates began to appear after about 4 hours, and a large amount ofwhite precipitates were formed after 12 hours.

Experiment 6.3

Docetaxel-castor oil drug-loaded fat emulsion: 100 mg of docetaxel, 300mg of castor oil, 40 mg of egg yolk lecithin and 80 mg of mPEG2000-DSPEwere taken and dissolved in chloroform, blown to dry in nitrogen anddried under vacuum. Then 20 ml of phosphate buffer solution was added toadjust pH to 7.4, hydrated for 1 h, homogenized for 5 min at 20000 r/minwith high speed shearing machine. The obtained drug-loaded fat emulsionwas detected by Malvern ZS laser particle size analyzer, and the averageparticle size thereof was 330 nm. The prepared drug-loaded emulsion hadpoor stability, white precipitates began to appear after about 1 hour,and a large amount of white precipitates appeared after 4 hours.

Experiment 6.4

Paclitaxel-hydrophobic excipient of example 1 drug-loaded fat emulsion:100 mg of paclitaxel, 300 mg of hydrophobic excipient obtained inexample 1, 40 mg of egg yolk lecithin, and 80 mg of mPEG2000-DSPE weredissolved in chloroform, blown to dry in nitrogen and dried undervacuum. Then 20 ml of phosphate buffer solution was added to adjust pHto 7.4, hydrated for 1 h, homogenized for 5 min at 20,000 r/min withhigh speed shearing machine. The obtained drug-loaded fat emulsion wasdetected by Malvern ZS laser particle size analyzer, and the averageparticle size thereof was 215 nm. And the drug-loaded fat emulsion canremain stable for about 72 h after being prepared, then a whiteprecipitate began to appear.

Experiment 6.5

Docetaxel-hydrophobic excipient of example 1 drug-loaded fat emulsion:100 mg of docetaxel, 320 mg of the hydrophobic excipient prepared inexample 1, 40 mg of egg yolk lecithin and 80 mg of mPEG2000-DSPE weredissolved in chloroform, blown to dry in nitrogen and dried undervacuum. Then 1 ml of phosphate buffer solution was added to adjust pH to7.4, hydrated for 1 h, homogenized for 5 min at 20,000 r/min with highspeed shearing machine. The obtained drug-loaded fat emulsion wasdetected by Malvern ZS laser particle size analyzer, and the averageparticle size thereof was 225 nm. And the drug-loaded fat emulsion canremain stable for about 1 day after being prepared, then a whiteprecipitate began to appear at about 19 h.

Experiment 6.6

Paclitaxel-hydrophobic excipient of example 2 drug loaded fat emulsion:100 mg of paclitaxel, 300 mg of hydrophobic excipient prepared inexample 2, 40 mg of egg yolk lecithin, and 80 mg of mPEG2000-DSPE weredissolved in chloroform, blown to dry in nitrogen and dried undervacuum. Then 20 ml of phosphate buffer solution was added to adjust pHto 7.4, hydrated in a 50° C. water bath for 1 h, homogenized for 5 minat 20,000 r/min with high speed shearing machine. The obtaineddrug-loaded fat emulsion was detected by Malvern ZS laser particle sizeanalyzer, and the average particle size thereof was 215 nm. And thedrug-loaded fat emulsion can remain stable for about 2 day after beingprepared, then a white precipitate began to appear at about 76 h.

Experiment 6.7

Docetaxel-hydrophobic excipient of example 2 drug-loaded fat emulsion:100 mg of docetaxel, 320 mg of the hydrophobic excipient prepared inexample 4, 40 mg of egg yolk lecithin and 80 mg of mPEG2000-DSPE weredissolved in chloroform, blown to dry in nitrogen and dried undervacuum. Then 1 ml of phosphate buffer solution was added to adjust pH to7.4, hydrated for 1 h, and homogenized for 5 min at 20,000 r/min withhigh speed shearing machine. The obtained drug-loaded fat emulsion wasdetected by Malvern ZS laser particle size analyzer, and the averageparticle size thereof was 210 nm. And the drug-loaded fat emulsion canremain stable for about 20 h after being prepared, then a whiteprecipitate began to appear.

Experiment 6.8

Paclitaxel-hydrophobic excipient of example 3 drug loaded fat emulsion:100 mg of paclitaxel, 300 mg of hydrophobic excipient prepared inexample 3, and 40 mg of egg yolk lecithin, 80 mg of mPEG2000-DSPE weredissolved in chloroform, blown to dry in nitrogen and dried undervacuum. Then 20 ml of phosphate buffer solution was added to adjust pHto 7.4, hydrated in a 50° C. water bath for 1 h, homogenized for 5 minat 20,000 r/min with high speed shearing machine. The obtaineddrug-loaded fat emulsion was detected by Malvern ZS laser particle sizeanalyzer, and the average particle size thereof was 235 nm. And thedrug-loaded fat emulsion can remain stable for at least 2 day afterbeing prepared, then a white precipitate began to appear at about 76 h.

Experiment 6.9

Docetaxel-hydrophobic excipient of example 3 drug-loaded fat emulsion:100 mg of docetaxel, 320 mg of the hydrophobic excipient prepared in theexample 3, 40 mg of egg yolk lecithin and 80 mg of mPEG2000-DSPE weredissolved in chloroform, blown to dry in nitrogen and dried undervacuum. Then 1 ml of phosphate buffer solution was added to adjust pH to7.4, hydrated in a 50° C. water bath for 1 h, homogenized for 5 min at20000 r/min with high speed shearing machine. The obtained drug-loadedfat emulsion was detected by Malvern ZS laser particle size analyzer,and the average particle size thereof was 220 nm. And the drug-loadedfat emulsion can remain stable for about 1 day and a half after beingprepared, then a white precipitate began to appear at about 32 h.

Experiment 6.10

Docetaxel-hydrophobic excipient of example 4 drug-loaded fat emulsion:100 mg of docetaxel, 320 mg of the hydrophobic excipient prepared inexample 4, 40 mg of egg yolk lecithin and 80 mg of mPEG2000-DSPE weredissolved in chloroform, blown to dry in nitrogen and dried undervacuum. Then 1 ml of phosphate buffer solution was added to adjust pH to7.4, hydrated for 1 h, homogenized for 5 min at 20,000 r/min with highspeed shearing machine. The obtained drug-loaded fat emulsion wasdetected by Malvern ZS laser particle size analyzer, and the averageparticle size thereof was 210 nm. And the drug-loaded fat emulsion canbe stable for about 22 h after being prepared, then a white precipitatebegan to appear.

According to the experimental result, when the castor oil is used as theoil phase, the drug-loaded fat emulsion prepared by the castor oil, thepaclitaxel and the docetaxel is relatively unstable, and whiteprecipitate is generated after about 1-4 h. When the modifiedhydrophobic excipient of the present application is used as an oilphase, the stability of the drug-loaded fat emulsion prepared by themodified hydrophobic excipient, paclitaxel and docetaxel generally canreach more than 20 h, which indicates that, forming the hydrophobicexcipient by introducing an aromatic ring and a carbamoyl group or anamide group into a hydrophobic compound can provide the hydrophobiccompound with a π-π function, thereby being beneficial for aromatic ringstacking between the hydrophobic excipient and the drug containing thearomatic group, so that they can combine with each other throughnon-covalent physical action. In addition, the carbamoyl group and theamide group can be combined with the drug in a non-covalent physical waythrough a hydrogen bond in a hydrophobic environment, so as to furtherimprove the stability of the drug-loaded fat emulsion.

According to the experimental results, under the same conditions, thestability of the drug-loaded fat emulsion prepared from docetaxel isworse than that of the drug-loaded fat emulsion prepared from paclitaxelbecause docetaxel is more hydrophilic than paclitaxel.

According to the experimental result, the stability of the drug-loadedfat emulsion prepared from the modified hydrophobic excipient preparedfrom the hydrogenated castor oil is higher than that of the drug-loadedfat emulsion prepared from the modified hydrophobic excipient preparedfrom the castor oil, which indicates that adopting the hydrogenatedcastor oil as the raw material to prepare the hydrophobic excipient isbeneficial to improve the stability of combination of hydrophobicexcipient and the drug.

The examples of the specific embodiment are preferred examples of thepresent application, and the scope of the present application is notlimited by these examples, so that all equivalent changes of thestructure, shape and principle of the present application are covered bythe protection scope of the present application.

What is claimed is:
 1. A drug-loaded emulsion, comprising a modifiedhydrophobic excipient having the following formula, a hydrophobic drugand a surfactant:

where R is a hydrophobic natural compound or a hydrophobic syntheticcompound with one to three hydroxyl groups (n=1-3); and R1 is an α-aminoprotecting group, and R2 is an amino acid side chain, wherein, when m=0,R is reacted with an amino acid derivative with a protecting group byesterification to form a hydrophobic excipient carrying the amino acidderivative with a protecting group; or when m=1, R is firstly introducedwith an amino acid linking arm of different chain lengths (l=1, 2, 4, 6)via an ester group, and then introduced with an amino acid derivativewith a protecting group.
 2. The drug-loaded emulsion according to claim1, wherein the modified hydrophobic excipient is protected amino acidester of the hydrophobic excipient or protected amino acid amide of thehydrophobic excipient amino acid ester.
 3. The drug-loaded emulsionaccording to claim 1, wherein the hydrophobic drug is a hydrophobic drugcapable of having an intermolecular interaction, including aromatic ringstacking, hydrogen bond or hydrophobic interaction, with the modifiedhydrophobic excipients, such as paclitaxel and docetaxel.
 4. Thedrug-loaded emulsion according to claim 1, wherein a ratio of thehydrophobic drug to the modified hydrophobic excipient is 0.01%(w/w)-99.9% (w/w) to 99.9% (w/w)-0.01(w/w), preferably 1% (w/w)-50%(w/w) to 99% (w/w)-50(w/w), and more preferably 1:1 to 1:5.
 5. Thedrug-loaded emulsion according to claim 1, wherein the surfactant is apharmaceutical surfactant excipient having a hydrophilic-lipophilicbalance (HLB) value in the range of 0 to
 40. 6. The drug-loaded emulsionaccording to claim 1, wherein the surfactant is a small molecule orlarge molecule pharmaceutical excipient with a function of solubilizingor emulsifying or wetting or foaming agent or defoaming agent ordetergent.
 7. The drug-loaded emulsion according to claim 1, wherein thesurfactant is a small molecule or large molecule pharmaceuticalexcipient with a function of stabilizing a nanometer structure.
 8. Thedrug-loaded emulsion according to claim 1, wherein the surfactant is acationic or anionic or nonionic surfactant.
 9. The drug-loaded emulsionaccording to claim 1, wherein the surfactant is phospholipid orcholesterol, or fatty acid with the chain length of C8-C22, or fattyacid salt with the chain length of C8-C22, sucrose fatty acid ester,sorbitan fatty acid (spans), polysorbate (Tweens) polyoxyethylene fattyacid ester (Myrij), polyoxyethylene fatty alcohol ether, orPEG-cholesterol derivative with different chain lengths, PEG-vitamin Esuccinate with different chain lengths, or PEG-phospholipid derivativewith different chain lengths, or PEG-diglyceride derivative withdifferent chain lengths, or any natural polymer pharmaceutical excipientor synthetic polymer pharmaceutical excipient with surface activity. 10.The drug-loaded emulsion according to claim 1, wherein the surfactantphospholipid is any one selected from a group consisting ofphosphatidylcholine (PC), Phosphatidylglycerol (PG),phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidicacid (PA), phosphatidylinositol (PI), eggphosphatidylcholine (EPC), eggphosphatidylglycerol (EPG), phosphatidylethanolamine (EPE),eggphosphatidylserine (EPS), egg phosphatidic acid (EPA), (eggphosphatidylinositol (EPI), soy phosphatidylcholine (SPC), soyphosphatidylglycerol (SPG), soyphosphatidylethanolamine (SPE), soyphosphatidylserine (SPS), (soy phosphatidic acid SPA), soyphosphatidylinositol (SPI), dipalmitoylphosphatidylcholine (DPPC),1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC),dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylglycerol(DPPG), dioleoylphosphatidylglycerol (DOPG),dimyristoylphosphatidylglycerol (DMPG), hexadecylphosphocholine (HEPC),hydrogenated soyphosphatidylcholine (HSPC),distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol(DSPG), dioleoylphosphatidylethanolamine (DSPE),palmitoylstearoylphosphatidylcholine (PSPC),palmitoylstearoylphosphatidylglycerol (PSPG),monooleoylphosphatidylethanolamine (MOPE),1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC),distearoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylserine(DPPS), 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS),dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine(DSPS), dipalmitoylphosphatidicacid (DPPA),1,2-dioleoyl-snglycero-3-phosphatidic acid (DOPA),dimyristoylphosphatidic acid (DMPA), distearoylphosphatidic acid (DSPA),dipalmitoylphosphatidylinositol (DPPI),1,2-dioleoylsn-glycero-3-phosphatidylinositol (DOPI),dimyristoylphosphatidylinositol (DMPI), distearoylphosphatidylinositol(DSPI), and a mixture thereof.
 11. The drug-loaded emulsion according toclaim 10, wherein the polyethylene glycol (PEG) with different chainlengths-the lipid derivative with the chain length of C8-C22 is asurfactant formed by connecting PEG with the chain length of 1-1000repeating units and lipid with the chain length of C8-C22 by an esterbond or an ether bond or an amide bond.
 12. The drug-loaded emulsionaccording to claim 11, wherein the PEG-phospholipid derivative withdifferent chain lengths is a surfactant formed by connecting PEG with achain length of 1-1000 repeating units and natural or syntheticphospholipid by an ester bond, an amide bond or a carbamoyl bond. 13.The drug-loaded emulsion according to claim 11, wherein, in a surfactantof the PEG-phospholipid derivative with different chain length preparedby connecting PEG with a chain length of 1-1000 repeating units with anatural or synthetic phospholipid by an ester bond or an amide bond or acarbamoyl bond, the natural or synthetic phospholipids is a natural orsynthetic phospholipid with a carbon chain length of 12-22.
 14. Thedrug-loaded emulsion according to claim 11, wherein, in a surfactant ofthe PEG-phospholipid derivative with different chain lengths prepared byconnecting PEG with the chain length of 1-1000 repeating units with anatural or synthetic phospholipid by an ester bond or an amide bond or acarbamoyl bond, the natural or synthetic phospholipid is a natural orsynthetic phospholipid having a saturated or unsaturated lipid chainwith a carbon chain length of 12-22.
 15. The drug-loaded emulsionaccording to claim 11, wherein, in a surfactant of the PEG-phospholipidderivative with different chain lengths prepared by connecting PEG withthe chain length of 1-1000 repeating units with a natural or syntheticphospholipid by an ester bond or an amide bond or a carbamoyl bond, thenatural or synthetic phospholipid is natural or synthetic cephalin. 16.The drug-loaded emulsion according to claim 1, wherein the naturalpolymer pharmaceutical excipient or synthetic polymer pharmaceuticalexcipient surfactant is a polysaccharide or polysaccharide derivative orpolyoxyethylene-polyoxypropylene (poloxamer) or protein with surfaceactivity.
 17. The drug-loaded emulsion according to claim 1, wherein thepharmaceutical excipient surfactant is a single pharmaceutical excipientor a combination of multiple pharmaceutical excipient surfactants. 18.The drug-loaded emulsion according to claim 1, wherein the surfactant islecithin or cholesterol or PEG-phospholipid derivative singlepharmaceutical excipient or a combination of multiple pharmaceuticalexcipient surfactants.
 19. The drug-loaded emulsion according to claim1, wherein the surfactant is a combination of lecithin and PEG-cephalinderivative.
 20. The drug-loaded emulsion according to claim 1, wherein aratio of the hydrophobic excipient-the hydrophobic drug to thesurfactant is (X+Y):Z, and Z %=100−(X+Y).
 21. The drug-loaded emulsionaccording to claim 20, wherein a ratio of the hydrophobic excipient-thehydrophobic drug to the surfactant is (X+Y):Z=(0-50%):(100-50%).